Investigating the link between REV-ERB and HIF-1a in Th17 cell function

摘要 自身免疫性疾病(即类风湿性关节炎(RA)、1型糖尿病(T1 DM)、多发性硬化症(MS)、 克罗恩病等。)影响到至少3%的美国人口，尽管这一数字似乎显著 自2020年以来不断增加。有趣的是，许多自身免疫性疾病在女性中的发病率不成比例。这些 疾病是慢性的，使人虚弱，而且常常危及生命。生物治疗学的最新进展 在许多患者中成功地减轻了这些慢性病的症状。然而，由于成本的原因， 与这些治疗相关的是，许多美国人仍然不接受治疗。事实上，最近的几份报告已经 描述了西班牙裔、非裔美国人和美洲原住民后裔妇女的健康差距，原因是 提供医疗保健和成本效益高的治疗方法。显然，对低成本疗法的需求尚未得到满足。 治疗自身免疫性疾病。为了开发治疗自身免疫性疾病的新疗法，我们需要进一步发展我们的 了解控制Th17激活和分化的生理和细胞机制 细胞。Th17细胞是产生致炎细胞因子白介素17a的CD4+淋巴细胞的一个亚型。 (IL-17a)。Th17细胞活性异常与多种自身免疫性疾病有关，包括多发性 硬化症、类风湿性关节炎、牛皮癣等。目前的许多生物疗法都是针对 由Th17细胞产生的白介素会减少异常的炎症过程。缺氧诱导因子-1是一种转录因子 这在Th17细胞的代谢调节中起着重要作用。有趣的是，核受体REV- Erb，通过与rort竞争来调节th17细胞的激活和分化，最近的工作是 我们的实验室发现，REV-ERB可以直接抑制HIF-1的表达，提供了一种两次打击的机制 抑制T细胞介导的自身免疫性疾病。该提案旨在调查REV-ERB 在缺氧诱导因子-1的表达中发挥作用，并确定T细胞在与和激活过程中发生的细胞变化 没有REV-ERB配体的存在。从这项工作中获得的数据将为 REV-ERB在T细胞生理学中的作用，并为未来的药物发现工作提供初步数据。

SUMMARY Autoimmune diseases (i.e., rheumatoid arthritis (RA), Type I Diabetes mellitus (T1DM), multiple sclerosis (MS), Crohn's disease, etc.) affect at least 3% of the US population, although this number appears to be significantly increasing since 2020. Interestingly, many autoimmune diseases occur disproportionately in women. These diseases are chronic, debilitating, and often, life threatening. Recent advances in biologic therapeutics have been successful in reducing symptoms of these chronic diseases in many patients. However, due to the costs associated with these treatments, many Americans still go untreated. In fact, several recent reports have described health disparities in women of Hispanic, African American, and Native American descent, due to availability of healthcare and cost-effective therapies. There is a clear unmet need for lower cost therapeutics for autoimmune diseases. To develop new therapies for autoimmune diseases, we need to further our understanding of the physiological and cellular mechanisms controlling activation and differentiation of Th17 cells. Th17 cells are a subtype of CD4+ lymphocytes that produce the pro-inflammatory cytokine interleukin 17a (IL-17a). Dysregulated activity of Th17 cells is associated with several autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, and others. Many of the current biologic therapies target the interleukins produced by Th17 cells to reduce aberrant inflammatory processes. HIF-1 is a transcription factor that plays an important role in the metabolic regulation of Th17 cells. Interestingly, the nuclear receptor REV- ERB, regulates both the Th17 cell activation and differentiation by competing with RORt, and recent work by our lab indicates that REV-ERB may directly repress the expression of HIF-1, providing a “two-hit” mechanism to suppressing T-cell mediated autoimmune diseases. This proposal aims to investigate the role that REV-ERB plays in HIF-1 expression and determine the cellular changes that occur in T-cells during activation with and without the presence of REV-ERB ligands. The data obtained from this work will provide novel insights to the role that REV-ERB plays in T-cell physiology, and provide preliminary data for future drug discovery efforts.